1. Field of the Invention
The present invention is directed to an improved process for the preparation of .alpha.-alkylidene-substituted lactones, and the Z and E isomers thereof.
2. Description of the Prior Art
There has been considerable interest in the preparation of .alpha.-alkylidene lactones in view of the recognized biological activity of .alpha.-methylenated-.gamma.- and .delta.-lactones. Synthetic routes to these products generally involve either (a) formation of the .alpha.-methylene or .alpha.-alkylidene lactone from acylic precursors containing all of the desired functional groups via a ring closure reaction; or (b) conversion of an existing group at the .alpha.-position on a preformed lactone ring to the corresponding .alpha.-methylene or .alpha.-alkylidene group. The present invention is directed to the latter type of reaction and, more specifically, relates to a process wherein the hydrogen and acetyl groups present in the .alpha.-position of a lactone ring are removed and replaced with an .alpha.-alkylidene moiety.
Numerous methods for the synthesis of .alpha.-methylene lactones are discussed in the review articles of P. A. Greico (Synthesis 1975, 67) and N. Petragnani et al. (Synthesis 1986, 157). None of the reactions described in either reference, however, deal with the preparation of .alpha.-alkylidene lactones. In fact, there is only one mention of the reaction of an acetyl group which is substituted at the s-position. Ueno et al (Tetrahedron Lett. 1978, 3753) describe the reaction of .alpha.-acetyl-.gamma.-butyrolactone with paraformaldehyde, lithium diisopropylamide in tetrahydrofuran to produce .alpha.-methylene-.gamma.-butyrolactone.
Ksander et al in (J. Org. Chem. 1977, 42, 1180) describe the preparation of .alpha.-alkylidene lactones by the reaction of ethyl oxalylbutyrolactones, with an aldehyde in the presence of aqueous sodium hydroxide. There is no suggestion by Ksander et al to the use of .alpha.-acyl-substituted lactones of any type for the reaction.
A multi-step synthesis which involves formulating .gamma.-lactone using sodium hydride and ethyl formate and then condensing the resulting enolate with an aldehyde to obtain the corresponding .alpha.-methylene-.gamma.-lactone is reported by Murray et al in J. Chem. Soc., Chem. Commun., 1984 at pp. 132-133.
Ono et al (J. Org. Chem. 1983, 48, 3678) report the conversion of an ester group which is substituted at the .alpha.-position on a .gamma.-butyrolactone ring to an .alpha.-isopropylidene moiety. The complex multi-step process involves reaction of the carbanion of an .alpha.-carboethoxy-.gamma.-butyrolactone and 2-chloro-2-nitropropane in the presence of a 150-watt tungsten lamp followed by the addition of sodium bromide and heat. In the only situation where Ono et al utilize a ring structure having an acetyl group in the .alpha.-position, namely, 2-acetylcyclopentanone, the corresponding .alpha.-isopropylidene cyclopentanone is not produced.
In view of the availability of .alpha.-acyl-substituted lactones, particularly .alpha.-acetyl-.gamma.-butyrolactones, it would be highly useful if a process were available wherein the acyl group could be readily replaced by an alkylidene moiety. It would be even more advantageous if the reaction was facile and utilized readily available reactants. These and other advantages are realized with the process of the present invention which will be described in more detail to follow.